PROJECT SUMMARY Comorbidity between alcoholism and other psychiatric disorders such as depression is extremely common. Determining how the circuitries of these conditions overlap is critical for the development of therapeutics targeting specific populations of alcoholic patients. Our group has recently determined a bidirectional relationship between alcohol exposure and stress-sensitivity which will be further investigated in this proposal. The neuroimmune system has gained attention in recent decades for its involvement in psychiatric conditions, indicating its signaling processes as promising targets for treating comorbid disorders. Of specific interest to our laboratory is the transcription factor nuclear factor ? light chain enhancer of activated B cells (NFkB). NFkB is activated following alcohol exposure and is implicated in behavioral processes such as consumption and reward. NFkB is also involved in the development of depressive-like symptoms that arise from exposure to social defeat stress (SDS), a major preclinical model of depression. As such, the multifaceted roles of NFkB suggest that this transcription factor may influence the circuitries underlying the development of both alcohol abuse and depression. To further study the role of NFkB in these processes, Aim 1 will examine the effects of SDS on alcohol reward via conditioned place preference (CPP) in NFkB-LacZ reporter mice. We expect that mice susceptible to defeat stress will display enhanced alcohol reward, and this elevated reward will associate with increased NFkB activity in regions of interest such as the nucleus accumbens. With selective inhibition of NFkB in the regions identified using the novel prodrug Daun02, we suspect that the increase in reward in susceptible animals will be attenuated. Aim 2 will explore the opposite phenomenon, that alcohol exposure increases sensitivity to subthreshold SDS. We expect that chronic alcohol exposure stimulates NFkB activity in specific regions of interest such as the basolateral and central amygdala, and selectively blocking NFkB in these regions with Daun02 will diminish sensitivity to SDS. We also suspect that lipopolysaccharide, a potent inducer of the neuroimmune system and NFkB activity, will mimic these effects and increase sensitivity to SDS. These studies will advance our current knowledge of the mechanisms underlying alcohol reward and stress- sensitivity as well as the involvement of NFkB in these circuitries. The results obtained from this proposal will further corroborate the promising therapeutic potential of targeting NFkB, as evidenced by its pivotal involvement in many important behavioral processes linking alcoholism and stress-sensitivity.